US5124321A - 17-halomethylene estratrienes - Google Patents

17-halomethylene estratrienes Download PDF

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Publication number
US5124321A
US5124321A US07/280,912 US28091288A US5124321A US 5124321 A US5124321 A US 5124321A US 28091288 A US28091288 A US 28091288A US 5124321 A US5124321 A US 5124321A
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United States
Prior art keywords
compound
estratriene
fluoromethylene
chloromethylene
acid
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US07/280,912
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English (en)
Inventor
Peter Jungblut
Rudolf Wiechert
Rolf Bohlmann
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Bayer Pharma AG
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Schering AG
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Assigned to SCHERING AKTIENGESELLSCHAFT reassignment SCHERING AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: JUNGBLUT, PETER, BOHLMANN, ROLF, WIECHERT, RUDOLF
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses

Definitions

  • the invention relates to 17-halomethylene estratrienes, processes for their production, pharmaceutical preparations containing these compounds, methods of treating estrogen deficiency symptoms and hormone-dependent tumors, and methods of contraception.
  • 17-halomethylene estratrienes are characterized by Formula I ##STR2## wherein R 1 is a hydrogen atom, a methyl or acyl group, and R 2 is a halogen atom.
  • Suitable acyl groups are physiologically compatible groups derived from acids customarily used for the esterification of hydroxy steroids. The identity and structure of the acyl moiety are not critical. Suitable acyl groups include organic carboxylic acids of 1-12 carbon atoms, e.g., hydrocarbon acids, pertaining to the aliphatic, cycloaliphatic, aromatic or aromatic-aliphatic series which can be saturated or unsaturated, mono- or poly-basic and/or substituted.
  • substituents examples include alkyl (e.g., of 1-4 C atoms), hydroxy, alkoxy (e.g., of 1-4 C atoms), oxo or amino groups (e.g., amino and mono- or dialkylamino (1-4 C-alkyl groups)) and halogen atoms.
  • alkyl e.g., of 1-4 C atoms
  • alkoxy e.g., of 1-4 C atoms
  • oxo or amino groups e.g., amino and mono- or dialkylamino (1-4 C-alkyl groups)
  • halogen atoms e.g., amino and mono- or dialkylamino (1-4 C-alkyl groups)
  • carboxylic acids of 1-12 carbon atoms include alkanoyl groups from formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, trimethylacetic acid, tertbutylacetic acid, cyclopentylacetic acid, diethylaminoacetic acid, lactic acid, succinic acid, adipic acid; other preferred groups include benzoic acid, nicotinic acid, morpholinoacetic acid, etc.
  • inorganic acids examples include sulfuric and phosphoric acids.
  • esters of succinic acid, adipic acid, sulfuric acid, and phosphoric acid can optionally be converted with an alkali into the water-soluble salts.
  • Hetero acyl groups can be derived from heterocyclic acids comprising 1-2 fused rings, wherein each ring contains 4-7 ring atoms and 1-2 hetero atoms, the hetero atoms comprising O, N and/or S.
  • Suitable acyl groups include that from pyrrolidino-, piperidino-, piperazino-, morpholinosulfonic acid, etc.
  • Suitable halogen atoms throughout the foregoing are fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • estratrienes substituted by halomethylene in the 17-position differ markedly from the estrones.
  • the compounds of general Formula I show a lower affinity to the estrogen receptors than estradiol and, as compared with estradiol, bring about increased cellular membrane and blood/lymphatic vessel permeability.
  • the compounds of Formula I show a lower affinity for the estrogen receptor.
  • 17-fluoromethylene-1,3,5(10)-estratrien-3-ol exhibits 1/40 of the uterotropic activity of estradiol, based on moist uterus weights including intrauterine fluid.
  • DNA content is employed as a measure of the uterus cell number, then approximately 1/70 of estradiol activity is found for 17-fluoromethylene-1,3,5(10)-estratriene.
  • the immature female rats receive once daily over 3 days estradiol or 17-fluoromethylene-1,3,5(10)-estratrien-3-ol subcutaneously. On the 4th day, the animals are sacrificed, and the uterus weight or the DNA content per uterus is determined.
  • a uterus weight of 67 mg is obtained with 0.1 ug of estradiol or with 4.2 ug of 17-fluoromethylene-1,3,5(10)-estratrien-3-ol.
  • a DNA content of 381 ug is the result with 0.1 ug of estradiol or with 7.3 ug of 17-fluoromethylene-1,3,5(10)-estratrien-3-ol.
  • estradiol or 17-fluoromethylene-1,3,5(10)-estratrien-3-ol Upon local administration of estradiol or 17-fluoromethylene-1,3,5(10)-estratrien-3-ol into the uterine lumen of a pig, a uterine edema is produced which is more strongly pronounced in case of the 17-fluoromethylene compound than in case of estradiol.
  • the extent of edema can be determined by ascertaining the albumin and DNA content of the uterus.
  • Intrauterine injection of 1 ⁇ 10 -6 -molar solutions (20-50 ml/uterus) of the compounds to be tested leads, after 120 minutes, in case of estradiol, to an increase in the albumin content of about 17 mg of albumin/1 mg of DNA and, in case of the corresponding 17-fluoromethylene compound, to an increase of 36 mg albumin/1 mg DNA.
  • test compound into a uterine horn of a female pig brings about edema formation only at that location; the untreated horn is not affected.
  • the compound is bound to the receptor without subsequent renewed synthesis of receptor.
  • the finding for the compounds of Formula I is an activity disproportionation indicating a lower activity in the cell nucleus by way of the estrogen receptor, with an edema formation that is unchanged as compared with estradiol.
  • the compounds of Formula I are substrates for intracellular enzymes, the products of which lead to an increase in cellular membrane and blood/lymphatic vessel permeability, which can be demonstrated as so-called "water imbibition" in the form of a massive edema in the target organ, the uterus.
  • These compounds are especially suitable for the treatment of climacteric complaints, as well as generally for the treatment of symptoms occurring due to defunctionalization of the second activity segment of estradiol.
  • the active compounds are preferably administered orally, e.g. to mammals including humans, but they can also be administered locally and parenterally.
  • the active compounds are processed according to conventional methods for the customary forms of administration together with the additives, excipients and/or solubilizers customary in galenic pharmacy.
  • the preferred oral administration especially suitable are tablets, dragees, capsules, pills, aqueous suspensions or alcoholic solutions, and for local and parenteral administration, especially ointments and, respectively, oily solutions, such as, for example, sesame oil or castor oil solutions which can additionally contain, if desired, a solubilizer, e.g., benzyl benzoate.
  • the concentration of active compound in the pharmaceutical preparations depends on the type of administration and the field of usage.
  • tablets, dragees, capsules or pills can contain 10-150 ⁇ g of active compound per dosage unit, and oily solutions or ointments can contain 1-20 ⁇ g of active compound per milliliter.
  • the oral form of administration contains 10-100 ⁇ g of active agent.
  • This antitumor activity can be demonstrated using any conventional protocol, e.g., as described in Science 137 (1962), 257-262.
  • the compounds of Formula I being substances with a selective estrogenic activity, can also be utilized in preparations for contraception, preferably in combination with a progestationally active hormone component, e.g., levonorgestrel, gestodene, or desogestrel.
  • a progestationally active hormone component e.g., levonorgestrel, gestodene, or desogestrel.
  • Forms of administration that can be given orally contain preferably 10-100 ⁇ g of a compound of Formula I and 50-500 ⁇ g of a strongly effective gestagen per day.
  • the compounds are administered analogously to the known compound Miorogynon.sup.(R).
  • 17-halomethylene estratrienes of Formula I can be prepared according to this invention by reacting an estrone of Formula II ##STR3## wherein R is a hydrogen atom or a methyl group, with a halomethylenylide, and optionally acylating a free hydroxy group.
  • the reaction with halomethylenylide takes place according to conventional methods, for example in an aprotic solvent, such as dimethyl sulfoxide, dimethylformamide, dioxane, tetrahydrofuran, or a mixture of these solvents at temperatures of between 20° and 40° C., a protective gas, such as nitrogen or argon being preferably employed during the reaction (Pure and Applied Chemistry 52 (1980) 771).
  • an aprotic solvent such as dimethyl sulfoxide, dimethylformamide, dioxane, tetrahydrofuran, or a mixture of these solvents at temperatures of between 20° and 40° C.
  • a protective gas such as nitrogen or argon being preferably employed during the reaction (Pure and Applied Chemistry 52 (1980) 771).
  • the halomethylenylide is suitably prepared in the reaction solution from halomethyltriphenylphosphonium salt with a base, such as sodium hydride, sodium hydroxide, potassium tert-butylate, sodium methylate or butyllithium (Journal Fluorine Chemistry 27 (1985) 85).
  • a base such as sodium hydride, sodium hydroxide, potassium tert-butylate, sodium methylate or butyllithium
  • halomethyltriphenylphosphonium salts are fluoromethyltriphenylphosphonium tetrafluoroborate and chloromethyltriphenylphosphonium chloride.
  • the subsequent optional acylation takes place according to conventional methods for esterification of phenolic hydroxy groups, preferably with pyridine/acid anhydride or pyridine/acid chloride, at room temperature (Ang. Chemie 90 (1978) 602).
  • the mixture is poured on water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 17-chloromethylene-3- [(tetrahydropyran-2-yl)oxy]-1,3,5(10)-estratriene which, as a crude product, is dissolved in 50 ml of methanol and heated under reflux for one hour with 2 g of oxalic acid. Then the product is precipitated with ice water/sodium chloride taken up in ethyl acetate, dried over sodium sulfate, and concentrated to dryness under vacuum.
  • Example 4 Analogously to Example 4, 1.0 g of 17-fluoromethylene-1,3,5(10)-estratrien-3-ol is reacted with 5 ml of butyric acid anhydride to form 1.03 g of 3-butyryloxy-17-fluoromethylene-1,3,5(10)-estratriene.
  • Example 4 Analogously to Example 4, 1.0 g of 17-fluoromethylene-1,3,5(10)-estratrien-3-ol is reacted with 5 ml of undecylic acid anhydride to produce 1.06 g of 17-fluoromethylene-3-undecyloxy-1,3,5(10)-estratriene.
  • Ten drops (0.5 ml) contain 50 ⁇ g of active compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US07/280,912 1987-12-07 1988-12-07 17-halomethylene estratrienes Expired - Fee Related US5124321A (en)

Applications Claiming Priority (2)

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DE19873741800 DE3741800A1 (de) 1987-12-07 1987-12-07 17-halogenmethylen-estratriene
DE3741800 1987-12-07

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US (1) US5124321A (enrdf_load_stackoverflow)
EP (1) EP0320438B1 (enrdf_load_stackoverflow)
JP (1) JP2636913B2 (enrdf_load_stackoverflow)
AT (1) ATE80893T1 (enrdf_load_stackoverflow)
AU (1) AU617140B2 (enrdf_load_stackoverflow)
CA (1) CA1324374C (enrdf_load_stackoverflow)
DE (2) DE3741800A1 (enrdf_load_stackoverflow)
ES (1) ES2045176T3 (enrdf_load_stackoverflow)
GR (1) GR3006579T3 (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008188A1 (en) * 1995-08-23 1997-03-06 Astra Aktiebolag Novel estrogens
US6018062A (en) * 1995-03-13 2000-01-25 Schering Aktiengesellschaft 17-difluoromethylene-estratrienes

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5773432A (en) * 1996-10-30 1998-06-30 Schering Aktiengesellschaft Method for lowering plasma levels of lipoprotein(a)
US6054446A (en) * 1997-12-24 2000-04-25 Sri International Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use
WO2006002907A1 (en) * 2004-06-29 2006-01-12 Jadolabs Gmbh Use of steroid-derived pharmaceutical compositions for treating disorders relating to pathological processes in lipid rafts

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4011314A (en) * 1974-10-14 1977-03-08 Schering Aktiengesellschaft 7-hydroxyestradiols

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536703A (en) * 1968-09-11 1970-10-27 Searle & Co N - (3 - alkoxy - 19 - norpregna - 1,3,5(10),17(20) - tetraen - 21 - yl)amines and derivatives thereof
BE787343A (fr) * 1971-08-10 1973-02-09 Hoffmann La Roche Procede pour la preparation de 17-(2-halogenoethylidene)- steroides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4011314A (en) * 1974-10-14 1977-03-08 Schering Aktiengesellschaft 7-hydroxyestradiols

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
B. Runnebaum et al., Female Contraception: Update and Trends, Springer Verlag, Berlin, 1988, pp. 64 90, 109 121, 122 128, and 129 140. *
B. Runnebaum et al., Female Contraception: Update and Trends, Springer-Verlag, Berlin, 1988, pp. 64-90, 109-121, 122-128, and 129-140.
Bestmann, Old and New Ylid Chemistry, Pure & App. Chem., vol. 52, pp. 771 788, Pergamon Press Ltd., 1980. *
Bestmann, Old and New Ylid Chemistry, Pure & App. Chem., vol. 52, pp. 771-788, Pergamon Press Ltd., 1980.
Burton et al., "A Practical Synthesis of Fluoromethyltriphenylphosphonium Salts," Journal of Fluorine Chemistry, 27 (1985) 85-89.
Burton et al., A Practical Synthesis of Fluoromethyltriphenylphosphonium Salts, Journal of Fluorine Chemistry, 27 (1985) 85 89. *
CA:111, 214810y (1989) Preparation . . . by Jungblut Peter et al. *
Hofle et al., "4-Dialkylaminopyridine als hochwirksame Acylierungskatalysatoren", Neue synthetische Methoden (25), pp. 602-615.
Hofle et al., 4 Dialkylaminopyridine als hochwirksame Acylierungskatalysatoren , Neue synthetische Methoden (25), pp. 602 615. *
Huggins et al., "Induction and Extinction of Mammary Cancer", Science, Jul. 27, 1962, vol. 137, No. 3526, pp. 257-262.
Huggins et al., Induction and Extinction of Mammary Cancer , Science, Jul. 27, 1962, vol. 137, No. 3526, pp. 257 262. *
PDR, 45th Edition, 1991, pp. 1070 1073. *
PDR, 45th Edition, 1991, pp. 1070-1073.
The Merck Index, Tenth Edition, 1983, p. 8921. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6018062A (en) * 1995-03-13 2000-01-25 Schering Aktiengesellschaft 17-difluoromethylene-estratrienes
RU2155770C2 (ru) * 1995-03-13 2000-09-10 Шеринг Аг 17-дифторметилен-эстратриены, соединения и способ их получения
US6136800A (en) * 1995-03-13 2000-10-24 Schering Aktiengesellschaft 17-Difluoromethylene-estratrienes
WO1997008188A1 (en) * 1995-08-23 1997-03-06 Astra Aktiebolag Novel estrogens
US6043236A (en) * 1995-08-23 2000-03-28 Astra Aktiebolag Estrogens

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DE3741800A1 (de) 1989-06-15
EP0320438B1 (de) 1992-09-23
DE3874865D1 (de) 1992-10-29
ES2045176T3 (es) 1994-01-16
ATE80893T1 (de) 1992-10-15
JP2636913B2 (ja) 1997-08-06
EP0320438A1 (de) 1989-06-14
AU2665288A (en) 1989-06-08
GR3006579T3 (enrdf_load_stackoverflow) 1993-06-30
CA1324374C (en) 1993-11-16
AU617140B2 (en) 1991-11-21
JPH01193295A (ja) 1989-08-03

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